Year-end Sale % OFF 
Abstract
Whole-genome sequencing allows rapid detection of drug-resistant Mycobacterium tuberculosis isolates. However, the availability of high-quality data linking quantitative phenotypic drug susceptibility testing (DST) and genomic data have thus far been limited. We determined drug resistance profiles of 176 genetically diverse clinical M. tuberculosis isolates from the Democratic Republic of the Congo, Ivory Coast, Peru, Thailand, and Switzerland by quantitative phenotypic DST for 11 antituberculous drugs using the BD Bactec MGIT 960 system and 7H10 agar dilution to generate a cross-validated phenotypic DST readout. We compared DST results with predicted drug resistance profiles inferred by whole-genome sequencing. Classification of strains by the two phenotypic DST methods into resistotype/wild-type populations was concordant in 73 to 99% of cases, depending on the drug. Our data suggest that the established critical concentration (5 mg/liter) for ethambutol resistance (MGIT 960 system) is too high and misclassifies strains as susceptible, unlike 7H10 agar dilution. Increased minimal inhibitory concentrations were explained by mutations identified by whole-genome sequencing. Using whole-genome sequences, we were able to predict quantitative drug resistance levels for the majority of drug resistance mutations. Predicting quantitative levels of drug resistance by whole-genome sequencing was partially limited due to incompletely understood drug resistance mechanisms. The overall sensitivity and specificity of whole-genome-based DST were 86.8% and 94.5%, respectively. Despite some limitations, whole-genome sequencing has the potential to infer resistance profiles without the need for time-consuming phenotypic methods.
Highlights
Whole-genome sequencing allows rapid detection of drug-resistant Mycobacterium tuberculosis isolates
The MGIT 960-based MICs were higher than the 7H10 agar dilution-based MICs
The results of MGIT 960 and 7H10 agar dilution-based phenotypic drug susceptibility testing (DST) methods were highly correlated and suitable to separate the resistotype from the wt populations
Summary
Whole-genome sequencing allows rapid detection of drug-resistant Mycobacterium tuberculosis isolates. The availability of high-quality data linking quantitative phenotypic drug susceptibility testing (DST) and genomic data have far been limited. And accurate drug susceptibility testing (DST) of M. tuberculosis isolates is vital to prevent the transmission of multidrug-resistant strains (MDR; resistance to rifampin and isoniazid) [1]. The World Health Organization (WHO) endorses line probe assays and the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) for the detection of rifampin resistance as a surrogate marker for multidrug resistance [7, 8] These molecular tests have high sensitivities for drugs with an established target(s) of resistance and for which only a few mutations are responsible for most resistance in clinico (e.g., rifampin and isoniazid) [4]. There is an urgent need to link genotypic and phenotypic drug resistance readouts to obtain a better understanding of the mechanisms influencing the evolution and spread of drug resistance in M. tuberculosis [3, 16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
